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Tuning PARP-1 retention and release on DNA breaks

Award Number: R01CA259037
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Tuning PARP-1 retention and release on DNA breaks - Breaks in the structure of DNA are a persistent stress on the integrity of the genome, and they pose a substantial risk of chromosomal rearrangement and genetic mutation that can challenge the well-being of an organism and promote the development of cancer. There are several cellular mechanisms that monitor the state of the genome and rapidly initiate repair mechanisms in response to DNA damage so that a healthy genome is passed on to the next generation. Poly(ADP-ribose) Polymerase-1, or PARP-1, is a primary responder to breaks in the structure of DNA. PARP-1 has a unique catalytic activity that synthesizes polymers of ADP- ribose as a posttranslational modification on target proteins, primarily on PARP-1 itself (automodification). Upon binding to DNA breaks, PARP-1 activity is “turned on” to modulate DNA damage repair pathways and thereby promote cell survival. In contrast, excessive DNA damage leads to an elevated level of PARP-1 activity that results in cell death. Regulation of PARP-1 activity is therefore a critical factor in determining the fate of a cell. Importantly, inhibitors of PARP-1 (PARPi) have recently emerged as promising therapeutic agents for the treatment of cancer and inflammation. Despite a growing interest in PARPi and the discovery of expanded roles for PARP-1 activity in DNA repair, transcriptional regulation, and apoptotic signaling, there are still limited insights into the mechanism of PARP-1 catalytic activity and regulation. The objective of this research program is to fill major gaps in our knowledge of how PARP-1 is activated, modulated by a critical accessory protein (HPF1), and subsequently silenced in the process of detecting DNA damage in healthy cells and how it can be best inhibited by small molecules in current efforts to target PARP-1 in cancer and inflammation. Hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and crystallography are the major structural tools that we will apply to understand the impact of PARPi on PARP-1 dynamics and how PARP-1 in the DNA damage response is initially activated and then subsequently silenced through automodification. The structural and protein dynamics experiments will be combined with biochemical analysis of PARP-1 catalysis and DNA binding, and cell-based analysis of PARP-1 function based on our structural and biochemical work. In addition, medicinal chemistry will be employed to engineer allosteric PARP-1 “trapping” into PARPi compounds in order to increase the efficacy of targeting this enzyme in the cancer clinic. Moreover, an emerging PARPi-based imaging approach using established tumor assays with breast cancer patient-derived xenografts will determine the degree to which the PARPi compounds that we generate engage/kill cancer cells and impact survival of mice carrying tumor xenografts. The proposed studies of PARP-1 activity and regulation will advance current models of PARP-1 biological functions and generate new small molecule tools that will advance the understanding of PARP-1 biology and potentially represent new medicines for the cancer clinic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $527,081 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	4	2/19/2025	NON-COMPETING CONTINUATION	$527,081
														Subtotal = $527,081

Issue Date FY: 2024 ( Subtotal = $540,155 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$28,428
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	3	2/21/2024	NON-COMPETING CONTINUATION	$511,727
														Subtotal = $540,155

Issue Date FY: 2023 ( Subtotal = $556,600 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	2	2/25/2023	NON-COMPETING CONTINUATION	$556,600
														Subtotal = $556,600

Issue Date FY: 2022 ( Subtotal = $599,450 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	1	3/1/2022	NEW	$599,450
														Subtotal = $599,450

Grand Total All Awards = $2,223,286

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Tuning PARP-1 retention and release on DNA breaks

Award Number: R01CA259037

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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